3-deoxy-11, 17-oxygenated-androstanes



, 2,927,109 S-DEOXY-l1,17-XYGENATED-ANDROSTANES john Company, Kalamazoo, Mich., a corporation of Delaware N 0 Drawing. Application July 31, 1959 Serial No. 830,722

23 Claims. (Cl. 260-43955) The new compounds and the processes of the present invention are illustratively represented by the following formulaer 1 t CH3 CH3 V. VI

wherein X is selected from the group consisting of the carbonyl radical C=O), the S-hydroxymethylene radical and the lowcnacyloxy methylene radical United States Patent 0 John C. Babcock, Portage, Mich., assignor to The Upand the acyl radical is that ofa hydrocarbon carhoxylic Z is a halogen having an atomic weight from 79 to 127,

the procedure disclosed methylandrostane -dihydroxy-l'lot-methylandrcstane (III) with an alkali inclusive, i.e., bromine or iodine, Z is a halogen having an atomic weight from 19 to 36, inclusive, i.e., fluorine or chlorine, and Z" is a halogen having an atomic weight from 19 to 127, inclusive, i.e., fluorine, chlorine, bromine or iodine.

The novel compounds of this invention are useful in the treatment of humans and other mammals as oral and parenteral anabolic agents of improved therapeutic ratio and as progestational agents. They also affect the secre tion of gonadotropins and thus regulate ovulation and endometreal and placental deveiopment and, particularly when used in conjunction with estrogens, -e.g., ethinylestradiol and/or androgens, e.g., Halotestin (Qua-fluorollfl-hydroxy-l7-methyltestosterone) reduce fertility, and are useful in the treatment of dysmenorrhea, amenorrhea, endometriosis, threatened abortion and related gynecological disorders. The compounds of this invention in addition have central nervous system depressing activity. The compounds can be administered in conventional dosage forms such as pills, tablets, and capsules for oral use or in conventional liquid forms as are used with natural and synthetic steroid hormones for injection.

The starting material for this invention, llfi-hydroxyandrostan-l7-one (i), can be prepared in accordance with in applicants US. Patent 2,881,188.

The process of the present invention comp-rises: treating l1B-hydroXyandrostan-l7-one (I) with a hypohalous acid (used per se or produced from a N-haloamide or N-haloimide in situ) and then with sulfur dioxide to obtain l7-keto-9(ll)-androstene (II); treating the l7-keto- 9(l1)-androstene (Ii) with an alkylating agent such as methyl magnesium bromide to produce 17,8-hydroxy- 17a-methyl-9(ll)-androstene (11b); treating the 17/3- hydroXy-l7oc-methy19(ll)-androstene (lib) with a hypohalous acid such as hypochlorous, hypohromous or hypoiodous acid to give 9ot-halo-11B,l7B-dihydroxy-l7oc- (Iii); treating the 9ot-h3lO-l113,

such as sodium hydroxide to obtain 9,llfiepoxyl7amethyl-17,8hydroxyandrostane (IV); treating the 9,11,8- epoxy-17u-methyl-l7/3-hydroxyandrostane (IV) with hydrochloric or hydrofluoric acid or other hydrogen halide releasing agent to yield 9a-halo-ll 3,l7B-dihydroXy-l7ocmethylandrostane .(V) and treating the 9a-halo-1LBJ7B- dihydroxy-l7u-methylandrostane (V) with an oxidizing agent such as chromic acid to obtain 9a-halo-l1-keto- 17a-methyl-l7fi-hydroxyandrostane (VI). 9oc-h21lO-11- keto-l7a-methyl-l7fi-hydroxyandrostane (VI) can also be produced by treating 9ot-halo115,17B-dihydroxy-17- inethylandrostane (Ill) with an oxidizing agent such as chromic acid. This brief description of the methods employed in the production of the compounds of Formula VI from (I) is only illustrative of the process which is more broadly disclosed in the examples.

The following examples are illustrative of the products and processes of this invention, but are not to be construed as limiting.

EXAMPLE 1 17-ket0-9(11 )-androstene (II) A solution of 5 g. of llB-hydroXyan-drostan-l7-one (I) (prepared in the manner disclosed in applicants U.S. Patent'2,88l,l88) dissolved in 25 ml. of pyridine was stirred with 3 g. of N-bromoacetamide for a period of 5 minutes with cooling. The mixture was saturated with sulfur dioxide gas until the orange color faded. It was then diluted with water and yielded 5 g. of colorless solid with a positive Beilstein test. The product was allowed to react overnight with 5 g. of zinc dust in 25 ml. of acetic acid. The crude product was diluted with water and chromatographed over Florisil synthetic magnesium silicate. Elution with 1% acetone in petroleum ether yielded 1.26 g. of 17-keto-9(11)-androstene with a melting point of 134 to 135 C. and an [al of +142 (chloroform). (Elution with 2% acetone in petroleum ether gave 1.86 g. of unreacted starting material.)

Analysis.-Calcd. for C I-1 C, 83.77; H, 10.36. Found: C, 83.52; H, 10.41.

ExAMPLE 2 17/3-hydr0xy-9(11 )-andr0stene (Ila) A solution prepared from 0.3 g. of 17-keto-9(11)- androstene (II) in 4 ml. of methanol was reduced with 0.15 g. of sodium borohydride in 1 ml. of methanol containing 2 drops of sodium hydroxide. The product (Ila) separated during the reaction and had a melting point of 162 to 165 C. and an [651D of +9 (chloroform) Analysis-Called; for C I-I 0: C, 83.15; H, 11.02. Found: C, 82.80; H, 11.05.

A solution of 17 8-hydroxy-9(l1)-androstene (Ila) in dry pyridine was heated with acetic anhydride under reflux until esterification was complete to yield 17fi-hydroxy- 9(11)-androstene 17-acetate. Similarly, 17fi-hydroxy-9- (11)-androstene is converted to other l7B-hydroxy-9(11)- androstene 17-acylates by esterification of the 17-hydroxy group, e.g., by reaction with the appropriate acid anhydride, acid chloride or bromide, ester by ester exchange, acid in the presence of esterification catalyst, etc. Examples of 17B-hydroxy-9(l1)-androstene 17-acylates prepared include those wherein the acyl group is the acyl radical of, for example, a lower-aliphatic acid, e.g., for mic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, Z-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, a-ethylisovaleric, or other hydrocarbon carboxylic acids containing from one to twelve carbon atoms, inclusive, e.g., cyclopropylidenacetic, cyclopentylformic, cyclopentylacetic, fl-cyclopentylpropionic, cyclohexylforinic, cyclohexylacetic, fl-cyclohexylpropionic, an aryl or alkaryl acid, e.g., benzoic, 2, 3, or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6, 3,4-, and 3,5-dimethylbenzoic, ethylbenzoic, 2,4,6- trimethylbenzoic, a naphthoic, 3 methyl 0c naphthoic, phenylacetic, phenylpropionic, etc.

EXAMPLE 3 17,8-hydr0xy-I7a-methyl-9 (1 1 -a ndr0'stene (IIb) A solution of 17-keto-9(1l)androstene (II) in benzene was added during a period of about one-half hour to a solution of methyl magnesium bromide in ether. The resulting mixture was stirred under nitrogen for about 8 hours, then cooled and decomposed with saturated ammonium chloride. Following dilution with ether and standing overnight the mixture was filtered. The filter cake was washed with ether then taken up in hydrochloric acid and extracted with ether. The combined ether extracts were pooled, washed with water, dried and evaporated to yield 17fi-hydroxy-l7u-methyl-9(11)-androstene, a crystalline solid.

A solution of 17fl-hydroxy-17a-methyl-9(11)-androstene (11b) in dry pyridine was heated with acetic anhydride under reflux until esterification was complete to yield 17;8-hydroxy-17a-methyl-9(11 )-androstene 17-acetate. Similarly, 17,3 hydroxy 17m methyl 9(11)- androstene is converted to other 17-acylates in addition to the acetate by esterification of the 17-hydroxy group, e.g., by reaction with the appropriate acid anhydride, acid chloride, ester by ester exchange, acid in the presence of an esterification catalyst, etc. esters that can be thus prepared include those named in the paragraph following Example 2.

EXAMPLE 4 17fl-hydroxy-1 7a-ethinyl-9 (1 1 -ana'rostene (Ilc) A solution of 17-keto-9(11) androstene (II) in dimethylsulfoxide was added to a solution of sodium acetylide in dimethylsulfoxide. After stirring the reaction mixture for about 15 hours at room temperature, ice was added and the mixture diluted with cold water. The resulting precipitate was washed with water, dried and purified by recrystallization to give 17fi-hydroxy-17w ethinyl-9(11)-androstene, a crystalline solid.

EXAMPLE 5 Qa-bromo-J] 13, 1 7,8-dihydroxy-17-methylandrostane ([11) To a solution of 17,8-hydroxy-17u-methyl-9(11)-androstene (11b) in acetone at about 15 C., N-bromoacetamide dissolved in water was added dropwise, with stirring. A dilute solution of perchloric acid was then slowly added at the same temperature. After about twenty minutes, there was added a sufiicient amount of a saturated aqueous solution of sodium sulfite to discharge the yellow color of the solution. The resulting mixture was then diluted with water thereby precipitating 90cbromo 115, 1713 dihydroxy 17 methylandrostan'e.

Similarly, esters of l7fi-hydroxy-l7-methyl-9(11)- androstane, e.g., an ester named in the paragraph following Example 2, preferably the acetate, are similarly converted to esters of 9tx-bromo-11fl, l7fi-dihydroxy-l7- methylandrostane.

Reacting 91x bromo 11,8, 175 dihydroxy 17- methylandrostane or a 17-ester thereof named above, with sodium iodide in acetone, according to techniques known in the art, is productive of 9a-iodo-11/3, 175-dihydroxy-l7-methylandrostane or a 17-ester thereof.

Examples of c bromo 11o, 17 3 dihydroxy 17 ethylandrostame and esters thereof are similarly prepared by substituting 17fi-hydroxy-17-ethyl-9(11)-androstene and esters thereof, respectively, as the starting steroid in the reaction described in Example 5.

Following the procedure of Example 5, but substituting 9(11)-androsten-17-one as the starting steroid, yields 9a-bromo-l 1 fl-hydroxyandrostan- 17-one.

In the reaction of Example 5, the N-bromoacetamide produces hypobromous acid in situ. Other N-bromoamides and N-bromoimides may be used or a solution of hypobromous acid per se may be used.

A solution of 9a-b1'omo-11B,17fi-dihydroxy-17a-methylandrostane (III) in methanol, was titrated with dilute aqueous sodium hydroxide. The resulting mixture was diluted with water and then chilled to about zero degrees centigrade thereby precipitating 9,11,8-epoxy-l7a-methyl- 17B-hydroxy-androstane.

Following the procedure of Example 6, but substituting 9u-bromo-11fi-hydroxyandrostan-l7-one as the starting steroid, yields 9,1lfi-epoxyandrostan-17-one.

In the same manner as described in Example 6, 17- esters of 9u-bromo-11 3,17,8-dihydroxy-17-methylandrostane, e. g., 9a-bromo-l lfi-hydroxy-17-methyltestosterone 17-acylates wherein the acyl radical is that of an acid named in the paragraph following Example 2 are converted to l7-esters of 9,1 1,6-epoxy-17-methyl-17fl-hydroxyandrostane.

9,1lfi-epoxy-l7amethyl-17,3-hydroxyandrostane and 17- esters thereof are also prepared by substituting 9ct-lOClO- 11,8,17fi-dihydroxy l7 methyland-rostane and 17 esters thereof, respectively, as the starting steroid in the reaction described in Example 6.

9,11 fi-epoxy-lh-ethyl-l7/8-hydroxy and 17-esters thereof are similarly prepared by substituting 9u-bromo-11B, 17fl-dihydroxy-17-ethylandrostane and 17-esters thereof as the starting steroid in the reaction described in Example 6.

EXAMPLE 7 9u-flu0ro-I 5,1 7,8-dihydr0xy-1 7-methylandrostane V) Add a cooled solution of 9,1lfi-epoxy-l7-methyl-17flhydroxyandrostane (IV) in methylene chloride to a large "excess of" anhydrous hydrogen fluoride in methylene chloride containing tetrahydrofuran. The mixture is stored the aqueous layer is extracted with methylene chloride. The combined methylene chloride solution is washed with water and then dried. The solvent is distilled from the dried solution and the residue crystallized from methylene chloride-Skellysolve B hexanes to give 9a-fiuoro-115,175- dihydroxy-17-methylandrostane.

9e-fiuoro-115,175-dihydroxy-17-ethylandrostane is prepared by substituting 9,ll5-epoxy-17-ethylandrostane as -the starting steroid in Example 7.

I Following the procedure of Example 7, but substituting 9,1l5-epoxyandrostane-l7-one as .the starting steroid, yields 9a-flt1010-1 15-hydroxyandrostan-l7-one.

9a fluoro 115,175 dihydroxy 17 methylandrostane dissolved in glacial acetic acid and a small amount of water is converted to 9a-fluoro-1Lketo-l75-hydroxy- 17-methylandrostane by reaction with chromic acid. 9 fluoro-l15-hydroxyandrostan-17-one is converted in the same manner to the corresponding ll-keto compound by reaction with chromic acid.

EXAMPLE 8 9u-flu0r0-115-hydr0xy-17a-methyl-175-hydr0xyandrostane 1.7-acetate (V) Following the procedure of Example 7, but substituting 9,115 epoxy 17a methyl 175 hydroxyandrostane .17-acetate as the starting steroid, there is thus produced 904 fluoro 115,175 dihydroxy l7 methylandrostane 17-acetate.

Following the procedure described in Example 8, but substituting as starting steroid another 17-.carboxylic acid ester of 9,115-epoxy-l7a-methyl-l75-hydroxyandrostane, e.g., a 9,ll5-epoxy-17a-methyl-l75-l'tydroxyandrostane 17-acylate wherein the acyl radical is that of an acid named in the paragraph following Example 2, there is thus produced other l7-esters of 9a-fluoro-l15,175-dihydroxy-17-methylandrostane, e.g., 9u-fluoro-1l5,l75-dihydroxy l7 methylandrostane 17 acylates wherein the acyl radical is that of a hydrocarbon, carboxylic acid containing from one to twelve carbon atoms, for example, a lower-aliphatic acid, e.g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trirnethylacetic,v Z-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, a-ethylisovaleric, cycl-opro-pylideneacetic, a cycloaliphatic acid, e.g., cyclopentylformic, cyclopentylacetic, 5-cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, 5-cyclohexylpropionic, an aryl or alkaryl acid, e.g., bcnzoic, 2-, 3-, or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dimethylbenzoic ethylbenzoic, 2,4,6-trimethylbenzoic, ot-naphthoic, S-methyl-unaphthoic, an aralkyl acid, e.g., 'phenylacetic, phenylpropionic, etc. v

Similarly, 9a fluoro 115,175 dihydroxy 17ccethylandrostane 17-acylatcs are prepared by substituting a 9,115-epoxy-l7ctethyl-175-hydroxyandrostane, 17-acylate, e.g., wherein the'acyl'radical is that of an acid named in the paragraph following Example 8, as the starting steroid in the reaction of Example 8.

ExA PLE9 9a-chl0r0-1 15-hydr0xy-1 7a-methyl-l 75-hydr0xyandrostane Following the procedure of Example 7, but substituting ;anhydrous hydrogen chloride for the hydrogen fluoride,

,; ample 2, are produced by substituting a 9,ll5-epoxy-17uniethyl-l75-hydroxyandrostane 17-acy1ate, e.g., wherein the acyl radical is that of an acid named in, the paragraph following Example 2, as the starting steroid in the reaction androstane or a 9,1,15-epoxy-17a-ethyl-175-hydroxyan drostane l7-acylate wherein the acyl radical is, for example, that of an acid named in the paragraph following Example 2, there is thus produced 9a-chloro-ll5,l75-dihydroxy-l7a-ethylandrostane and 9a-chloro-115,175-dihydroxy-1'7a--ethylandrostane 17-acylates.

The 9a-chloroand 9e -fiuoro-115-hydroxy-17-alkyltestosterone 17-acylates named above are also prepared by esterification of the corresponding free 17-hydroxy compounds in the manner described in the paragraph following Example 2. l

EXAMPLE 10 9ct-flMOI0-11k6tO-l 7a-methylJ 7'5Jtydroxy androstane (VI) To a solution of 9a-fluoro-ll5,175-dihydroxy-l7amethylandrostane (V) in glacial acetic acid was added a solution of chromium trioxide and water in acetic acid. The mixture was maintained at room temperature for several hours and then methanol was added to destroy excess chromium trioxide. Water was added to produce a precipitate which was filtered, washed with water. and then dried to give 9a-fluoro-11-keto5l7a-methyl-l75-hydroxyandrostane, a crystalline solid. 7

Following the procedure of Example 10, but substituting 9u-fluoro-l15-hydroxyandrostan-17-one as the starting steroid, yields 9 a-fluoro-l1,17-diketoandrostane.

Following the procedure described in Example 10,.but substituting as starting steroid a 9a-fiuoro.-115,175-dihydroxy-l7a-methylandrostane 17-acylate named in the paragraph following Example 2, there is thus-produced esters of 9m-fluoro-11-keto-l7u-methybl75-hydroxyandrostane, e.g., 9a-fluoro-11-keto-17a-methyl-175-hydroxyandrostane 17-acylates wherein the acyl radical is, for example, that of an acid named in the paragraph following Example 2. V

Similarly, substituting 9a-chloro-l15,175-dihydroxy- 17tt-II1BthYl21l'ldt0St3I16 as the starting steroid in the reaction described in Example 10, there is thus produced 9achloro-l l-keto-l 7u-methyl-l 75-hydroxyandrostane..

Substituting 90c fluoro -f 115,175 dihydroxy 17ccethylandrostane or 9a-fiuoro 1l5-hydroxy-17wethylandrostane l7-acylates wherein the acyl radical is, for 'example, that of an acid named in the paragraph following Example 2 as the starting steroid in Example 10, there is thus produced 9a-fiuoro-11-keto-l7a-ethyl-175-hydroxyandrostane and 9ot-fluorc-1ll-:eto-17a-ethyl-l75-hydroxyandrostane 17-acylates. The 9oc-chloro-ll-keto-17a-ethyl- 175-hydroxyandrostane and 17-acylates thereof are similarly prepared from the corresponding 9a-chloro-1l5- hydroxy compounds.

.f EXAMPLE 11 Qoubromo-II] -ket0-l 7u-methyl-1 75-Ity'dr0xyandr0stane Pollowing'the procedure of Example 10, but substituting 9a bromo-l15,175-dihydroxy-17u-methylandros tane (III) or 9a-iodo-115,l75-dihydroxy-17-methylandrostane as the starting steroid, therev is thus produced 9a-bromo-1l-keto-17ot-methyl-l75=hydroxyandrostane or 9a-iodo-1 l-keto- 17 a-methyl-l7 5-hydroxyandrostane.

EXAMPLE 12 V I 9a-brom0-115J 75-dihydr0xyandr0st ane (HI) Following the procedure of Example 5, but substituting 175-hydroxy-9(l1)-androstene 17-acetate (Example 2) as the starting steroid, there is thus produced bromc-l15,175-dihydroxyandrostanc 17-acetate.,0ther 17- acylates of -hydroxy-9( 11),-androstene including those l 7-acylates listed and prepared as, in the paragraph following Example 2, are similarly converted to l7-a'cyla'tes androstane.

I androstane.

7 of 9e-bromo-l1,8,l71S-dihydroxyandrostane. -9 x-bromol113,l7fl-dihydroxyandrostane is then produced by bydrolysis of the l7-acylates, preferably the acetate, with a dilute solution of hydrobromic acid in methanol.

Reacting 9ot-bromo-l1B,17B-dihydroxyandrostane or a l'i-acylate thereof named in the paragraph following EX- "ample 2, with sodium iodide in acetone, according to techniques known in the art, is productive of 9a-1odol1B,l7fi-dihydroxyandrostane or a l7-acylate thereof named in the paragraph following Example 2.

7 EXAMPLE 13 9,1lfl-epoxy-1 7fi-hydroxyandrostane (1V) Following the procedure of Example 6, but substituting '9a-bromo-11,6,175-dihydroxyandrostane as the starting steroid, there is thus produced 9,11B-epoxy-17B-hydroxyandrostane.

The 17-acylates of 9,1lB-epoxy-l7fl-hydroxyandrostane are prepared by refluxing a solution of a 9ot-bromo-l1/3,

17B-dihydroxyandrostane l7-acylate in methanol containing sodium acetate for 6 to 24 hours. After addition of water, the product is collected by filtration, washed 'with water and dried to give a 9,ll;3-epoxy-l7,B-hydroxy- EXAMPLE 14 9a-flu0r0-1 1,8,1 7fl-dihydroxyandrostane (V) Following the procedure of Example 7, but substituting 9,1lfi-epoxy-17,8-hydroxyandrostane as the starting steroid, there is thus produced 9a-fluoro-l1,8,17,8-dihydroxy- Following the procedure of Example 7, but substituting the starting steroid, there is thus produced 9u-fluoro-11B,17/3- dihydroxyandrostane l7-acetate.

Other l7-acylates of 9a-fluoro-11,8,l7/8-dihydroxyandrostane including those l7-acy1ates listed and prepared as in the paragraph following Example 2 are similarly converted to l7-acylates of 9u-fluoro-115,17,3-dihydroxy- EXAMPLE 16 I 9a-chlor0-1 15,17,3-dihydroxyandrostane Following the procedure of Example 7, but substituting anhydrous hydrogen chloride for the hydrogen fluoride,

there is thus produced 9ot-chloro-ll 8,17,8-dihydroxyan- EXAMPLE 17 9u-flu0r0-1]-keto-17fl-hydroxyandrostane VI) To a solution of 9afluoro-11,8,17fl-dihydroxyandrostane 17-acetate (Example 15) in acetic acid is added chromium trioxide in glacial acetic acid and a small amount of water. The mixture is maintained at room temperature for a period of .about 16 hours and then diluted with water. The resulting precipitate is recrystallized from methanol-water to give 9u-fiuoro-1l-keto-17B-hydroxyandrostane 17-acetate.

Following the procedure of Example 17, but substituting as starting steroid a 9a-fluoro-l1fl,l7B-dihydroxyandrostane 17-acylate wherein the acyl radical is that of an acid named in the paragraph following Example 2, there is thus produced a 9a-fluoro-11-keto-17B- hydroxyandrostane 17-acylate wherein the acyl radical is that of an acid named in the paragraph following Example 2.

Similarly, 9oc-chloro-l15,17,6-dihydroxyandrostane l7- acyla tes can be converted to the corresponding 9u-chlor'o- 1l-keto-l7/3-hydroxyandrostane 17-acylates.

Saponification of 9a-fluoro-1l-keto-17fi-hydroxyandrostane 17-acetate with a molar equivalent excess of sodium bicarbonate, sodium hydroxide, or hydrochloric acid in a mixture of methanol and water is productive of 9oc-flll0IO-1 1-keto-17 fi-hydroxyandrostane.

Saponification in a similar manner of other 9m-fluoro- 11-keto-l7 8 hydroxyandrostane 17-acylates also yields 9a-fluoro-1 1-keto-175-hydroxyandrostane.

Similarly, 9oc-Cl'll0l0 11 keto-l7fl-hydroxyandrostane 17-acylates can be converted to 9a-chloro-ll-keto-l7flhydroxyandrostane. V I

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

I claim:

1. 9(11)-androstene of the following formula:

wherein X is selected from the group consisting of the carbonyl radical C=O), the fl-hydroxymethylene and the lower-acyloxy methylene radical and the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, and Y is selected from the group consisting of hydrogen and a lower hydrocarbon radical.

2. 17-ketto-9(11)-androstene of the following formula:

CH3 CH3 A. member of .the group consisting of IVB-hydroxy- 2(l1) .-androstene of the'following formula:

and the l7-acylates thereof wherein the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

4. 17 3-hydr0Xy-9( 1 1 -androstene.

5. l7B-hydoxy-l7u-methyl-9(11)-androstenc.

6. 17B hydroxy 17a methyl 9(11) androstene 17-acetate.

7. 17B hydroxy 17cc ethinyl 9(11) androstene of the following formula:

CH3 Y l I H 8. 9a-halo-androstane of the following formula:

wherein R is selected from the group consisting of the carbonyl radical C=O) and the fi-hydroxymethylene radical Z" is a halogen having an atomic weight from 19 to 127, inclusive, X is selected from the group consisting of the carbonyl radical C=O), the B-hydroxymethylene radiand the lower-acyloxy methylene radical O Acy] and the acyl radical is that of a hydrocarbon carboxylic acid containing from one 'to twelve carbon atoms, inclusive, and Y is selected from the group consisting of hydrogen and a lower hydrocarbon radical.

9. A member of the group consisting 9m' -brbmqw l1,6,l7fi dihydroxyandrostane of the" following formula and the 17-acylates thereof wherein the acyl' radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

10. 9u-bromo-1 15, l7fl-dihydroxyandrostane.

11. 9a-bromo-1 l-ketol7p-hydroxyandrostane.

12. 9,11,8-epoxy-androstane of the following formula:

wherein X is selected from the group consisting of the carbonyl radical C=O), the B-hydroxymethylene radi-- and the lower-acyloxy methylene radical and the acyl radical is that of a hydrocarbon carboxylicr acid containing from one to twelve carbon atoms, in-- elusive, and Y is selected from the group consisting of hy-- drogen and a lower hydrocarbon radical.

13. 9,1 Iii-epoxy-l7-kctoandrostane.

15. 9,1 1 ,B-epoxy-l 7 fi-hydroxy- 17 a-methylandrostane.

16. 9a-fluoro-11,8,17B-dihydroxyandrostane of the following formula:

F. OHa,

l I H '1Lketo-l7fl hydroxyandrostane of the following formula:

2,927,109 11 12 22..A member of the group consisting of 9a-fluoroand the 17-acylates thereof wherein the acyl radical is that of a hydrocarbon carboxylic acid containing from CH3 one to twelve carbon atoms, inclusive.

OH 23. 9a-fluoro-11 keto 17B hydroxy 17 methylan- I 5 drostane. f References Cited in the file of this patent CH UNITED STATES PATENTS Sondheimer et a1 Feb. 26, 1957 OTHER REFERENCES Herr et al.: Journal of Amer. Chem. Soc. (1955) 5 vol.

77, pages 4889 relied on. I 

12. 9,11B-EPOXY-ANDROSTANE OF THE FOLLOWING FORMULA: 